Towards Understanding Deterioration in Systemic Right Ventricular Function in the Setting of Tricuspid Regurgitation: Is There a Point of No Return?

Need for Directed Therapy for the Systemic Right Ventricle

The field of adult congenital heart disease (ACHD) has continued to expand over the last few decades, with adults now outnumbering children living with congenital heart disease (CHD).^1,2 Although many of these patients have undergone surgical intervention which result in a relatively “normal” circulation, a large percentage are left with persistent anatomic and physiologic abnormalities when compared with the general population. Prime examples are those with a systemic right ventricle (sRV), such as patients with d-transposition of the great arteries (D-TGA) who have undergone an atrial switch operation or those with congenitally corrected transposition (ccTGA). Morphologic differences exist between the right and left ventricles, including fibre orientation, mechanism of contraction, and so on, as the right ventricle typically pumps against the low pressure/resistance pulmonary circulation.^3,4 In patients with an sRV, however, long-term adaptive mechanisms guide its response and ongoing ability to function in the systemic circulation.

In parallel to the increase in patients with ACHD, there have been tremendous strides in heart failure therapy in adult cardiac patients, with several newer therapeutic options now widely available. However, the impact of these drugs for both paediatric and adult patients with CHD remains less clear.⁵ The aforementioned differences between the right and left ventricles further complicate extrapolation of existing heart failure literature onto the ACHD population with an sRV.^6,7 Finally, imaging assessment of the right ventricle remains challenging.⁸ Because echocardiography is more widely available than cardiac magnetic resonance imaging (CMR), many studies evaluate right ventricular response to heart failure medications with echocardiography alone, but the gold standard for the structural and functional evaluation of the right ventricle remains CMR. Furthermore, only with CMR is accurate quantification of tricuspid regurgitant fraction (TRF) possible, which is helpful for stratification of the degree of insufficiency in patients with an sRV.⁹

Insights From Quantification of Tricuspid Insufficiency Into Right Ventricular Dysfunction

In this issue of CJC Pediatric & Congenital Heart Disease, Goto et al.¹⁰ explore the ability of tricuspid regurgitation (TR) quantification to predict deterioration in sRV systolic function over time in patients maintained on either angiotensin-converting enzyme inhibitors or angiotensin receptor blockers (ACE-I/ARB) therapy. The authors recognize that, to date, most studies assessing the sRV response to ACE-I/ARB have not shown benefit, but they hypothesize that due to the use of echocardiography and nonprotocoled assessments, these studies may not have been sufficient to demonstrate any response.^6,11 They studied 17 adults with either ccTGA or D-TGA after atrial switch who were maintained on ACE-I/ARB and underwent serial standardized CMR examinations at their institution from 2012 to 2022. The primary outcome was decline in systemic right ventricular ejection fraction (sRVEF).

Among their cohort, 3 patients experienced the primary endpoint. On both univariate and multivariate analyses, only TRF was an independent predictor of decline in sRVEF. Furthermore, stratification of patients by mild vs moderate/severe TR on the initial CMR revealed that, for those with mild TR, their sRVEF improved significantly in contrast that of patients with moderate/severe TR. This association held true whether patients who underwent tricuspid valve replacement were included or not in their analysis. For their cohort, a receiver operating curve showed that a cutoff point of 21.6% for the TRF provided optimal ability to predict sRVEF deterioration.

Strengths and Limitations of the Study

The authors are commended for using CMR for the assessment of systemic right ventricular function and TR. Although 3D echocardiography holds promise for more accurate assessment of right ventricular ejection fraction, both 2D and 3D echocardiography are limited by acoustic windows. Right ventricular longitudinal parameters (global longitudinal strain, tricuspid annular plane systolic excursion) have not consistently demonstrated correlation with systemic RV systolic function by CMR.¹² Tricuspid valve regurgitation on echocardiogram, in most cases, is reported as a qualitative, subjective designation. Thus, as we seek both accuracy and reproducibility within imaging studies and comparability across scientific reports, a more objective assessment of these measures via CMR is helpful.

Given the natural history tending towards deterioration of sRV function over time, the present study’s finding of improved RV systolic function in those with mild TR at follow-up CMR is notable. The contributing factors to this finding are unclear. Utilization of an ACE-1 or ARB is suggested as a possibility, although various confounding factors related to the retrospective nature of the study as well as the absence of a control group prevent definitive conclusions regarding the underlying cause. The authors acknowledge that the prior literature has been mixed regarding response of sRV to heart failure therapy.^11,13,14 Given that Goto's study was not designed to directly determine potential drug benefit, we agree with them that more rigorous prospective studies are needed.

Across studies, sRV end-diastolic dimensions and sRV systolic dysfunction are consistently associated with the outcomes of death, cardiac transplantation, and need for mechanical circulatory support.15, 16, 17 Thus, determination of potential predictors of deterioration in RV function is a meaningful undertaking. Prior studies using echocardiography have found that the degree of TR correlates with, and may be predictive of, RV systolic dysfunction and even mortality.^15,18 The Goto et al. study’s suggestion that a TRF of around 22% (moderate regurgitation) is a cutoff point is generally in line with previous studies that found statistical significance. Yet, it is novel in that it uses a more objective and quantitative assessment of both TR and RV function by CMR as opposed to more subjective assessment on echocardiogram. In addition, this study follows RV function over time as opposed to a single time point, a necessary step to establish predictability. Although the small sample size limits the generalizability of the findings, for this specific patient group, 17 patients are a reasonable cohort, albeit with increased potential for select outliers to influence results. The authors acknowledge the potential for confounding factors, and it would be interesting to know, at a granular level, potential explanatory etiologies for the notable changes in select patient cases, particularly given that their study group, on average, experienced improvement in RV systolic function over time. It is also relevant to note that, secondary to the small sample size, true multivariate analysis is not feasible without the risk of model overfitting, and confidence intervals in the study’s limited regression model are broad with the confidence interval for the odds ratio of TR fraction including 1.0.

Conclusions

As our field moves forward, the quest for precision medicine and patient-specific therapy will continue to evolve. Accurate evaluation of both valvar regurgitation and ventricular function is paramount to risk stratification and therapy selection. As Goto et al.¹⁰ point out in the present work, the ACHD population with sRV present unique challenges, and their study offers hope that ACE-I/ARB may benefit subsets of these patients. More work is needed to validate these results as well as to clarify the role of other heart failure medications, including not only β-blockers as they discussed, but also newer agents such as angiotensin receptor/neprilysin inhibitors and sodium-glucose transport protein 2 inhibitors, for patients with sRVs.